Dificid

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CLINICAL PHARMACOLOGY

Mechanism of Action

Pharmacodynamics

Fidaxomicin acts locally in the gastrointestinal tract on
C. difficile. In a dose-ranging trial (N=48) of fidaxomicin using 50 mg, 100
mg, and 200 mg twice daily for 10 days, a dose-response relationship was
observed for efficacy.

Pharmacokinetics

The pharmacokinetic parameters of fidaxomicin and its
main metabolite OP-1118 following a single dose of 200 mg in healthy adult
males (N=14) are summarized in Table 2.

*Tmax, reported as median (range)
Cmax, maximum observed concentration; Tmax, time to maximum observed
concentration; AUC0-t, area under the concentration-time
curve from time 0 to the last measured concentration; AUC0-∞, area under
the concentration-time curve from time 0 to infinity; t½, elimination
half-life

Absorption

Fidaxomicin has minimal
systemic absorption following oral administration, with plasma concentrations
of fidaxomicin and OP-1118 in the ng/mL range at the therapeutic dose. In
fidaxomicin-treated patients from controlled trials, plasma concentrations of
fidaxomicin and OP-1118 obtained within the Tmax window (1-5 hours) were
approximately 2- to 6-fold higher than Cmax values in healthy adults. Following
administration of DIFICID 200 mg twice daily for 10 days, OP-1118 plasma
concentrations within the Tmax window were approximately 50%-80% higher than on
Day 1, while concentrations of fidaxomicin were similar on Days 1 and 10.

In a food-effect study involving
administration of DIFICID to healthy adults (N=28) with a high-fat meal versus
under fasting conditions, Cmax of fidaxomicin and OP-1118 decreased by 21.5%
and 33.4%, respectively, while AUC0-t remained unchanged. This decrease in Cmax
is not considered clinically significant, and thus, DIFICID may be administered
with or without food.

Distribution

Fidaxomicin is mainly confined
to the gastrointestinal tract following oral administration. In selected
patients (N=8) treated with DIFICID 200 mg twice daily for 10 days from
controlled trials, fecal concentrations of fidaxomicin and OP-1118 obtained
within 24 hours of the last dose ranged from 639-2710 μg/g and 213-1210
μg/g, respectively. In contrast, plasma concentrations of fidaxomicin and
OP-1118 within the Tmax window (1-5 hours) ranged 2-179 ng/mL and 10-829 ng/mL,
respectively.

Metabolism

Fidaxomicin is primarily transformed by hydrolysis at the
isobutyryl ester to form its main and microbiologically active metabolite,
OP-1118. Metabolism of fidaxomicin and formation of OP-1118 are not dependent
on cytochrome P450 (CYP) enzymes.

At the therapeutic dose, OP-1118 was the predominant
circulating compound in healthy adults, followed by fidaxomicin.

Excretion

Fidaxomicin is mainly excreted in feces. In one trial of
healthy adults (N=11), more than 92% of the dose was recovered in the stool as
fidaxomicin and OP-1118 following single doses of 200 mg and 300 mg. In another
trial of healthy adults (N=6), 0.59% of the dose was recovered in urine as
OP-1118 only following a single dose of 200 mg.

Specific Populations

Geriatric

In controlled trials of patients treated with DIFICID 200
mg twice daily for 10 days, mean and median values of fidaxomicin and OP-1118
plasma concentrations within the Tmax window (1-5 hours) were approximately 2-
to 4-fold higher in elderly patients ( ≥ 65 years of age) versus
non-elderly patients ( < 65 years of age). Despite greater exposures in
elderly patients, fidaxomicin and OP-1118 plasma concentrations remained in the
ng/mL range [see Use In Specific Populations].

Gender

Plasma concentrations of fidaxomicin and OP-1118 within
the Tmax window (1-5 hours) did not vary by gender in patients treated with
DIFICID 200 mg twice daily for 10 days from controlled trials. No dose
adjustment is recommended based on gender.

Renal Impairment

In controlled trials of patients treated with DIFICID 200
mg twice daily for 10 days, plasma concentrations of fidaxomicin and OP-1118
within the Tmax window (1-5 hours) did not vary by severity of renal impairment
(based on creatinine clearance) between mild (51-79 mL/min), moderate (31-50
mL/min), and severe ( ≤ 30 mL/min) categories. No dose adjustment is
recommended based on renal function.

Hepatic Impairment

The impact of hepatic impairment on the pharmacokinetics
of fidaxomicin has not been evaluated. Because fidaxomicin and OP-1118 do not
appear to undergo significant hepatic metabolism, elimination of fidaxomicin
and OP-1118 is not expected to be significantly affected by hepatic impairment.

Drug Interactions

In vivo studies were conducted to evaluate intestinal
drug-drug interactions of fidaxomicin as a P-gp substrate, P-gp inhibitor, and
inhibitor of major CYP enzymes expressed in the gastrointestinal tract (CYP3A4,
CYP2C9, and CYP2C19).

Table 3 summarizes the impact of a co-administered drug
(P-gp inhibitor) on the pharmacokinetics of fidaxomicin [see DRUG
INTERACTIONS].

Table 3: Pharmacokinetic Parameters of Fidaxomicin and
OP-1118 in the Presence of a Co-Administered Drug

Fidaxomicin had no significant
impact on the pharmacokinetics of the following coadministered drugs: digoxin
(P-gp substrate), midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate),
and omeprazole (CYP2C19 substrate). No dose adjustment is warranted when
fidaxomicin is co-administered with substrates of P-gp or CYP enzymes.

Microbiology

Spectrum of Activity

Fidaxomicin is a fermentation product obtained from the
Actinomycete Dactylosporangium aurantiacum. In vitro, fidaxomicin
is active primarily against species of clostridia, including Clostridium
difficile.

Mechanism of Action

Mechanism of Decreased Susceptibility to Fidaxomicin

In vitro studies indicate a low frequency of spontaneous
resistance to fidaxomicin in C. difficile (ranging from < 1.4 × 10-9
to 12.8 × 10-9). A specific mutation (Val-ll43-Gly) in the beta
subunit of RNA polymerase is associated with reduced susceptibility to
fidaxomicin. This mutation was created in the laboratory and seen during
clinical trials in a C. difficile isolate obtained from a subject
treated with DIFICID who had recurrence of CDAD. The C. difficile isolate
from the treated subject went from a fidaxomicin baseline minimal inhibitory
concentration (MIC) of 0.06 μg/mL to 16 μg/mL.

Cross-Resistance/Synergy/Post-Antibiotic Effect

Fidaxomicin demonstrates no in vitro cross-resistance
with other classes of antibacterial drugs. Fidaxomicin and its main metabolite
OP-1118 do not exhibit any antagonistic interaction with other classes of antibacterial
drugs. In vitro synergistic interactions of fidaxomicin and OP-1118 have been
observed in vitro with rifampin and rifaximin against C. difficile (FIC
values ≤ 0.5). Fidaxomicin demonstrates a post-antibiotic effect vs. C.
difficile of 6-10 hrs.

Susceptibility Testing

The clinical microbiology laboratory should provide
cumulative results of the in vitro susceptibility test results for
antimicrobial drugs used in local hospitals and practice areas to the physician
as periodic reports that describe the susceptibility profile of nosocomial and
community acquired pathogens. These reports should aid the physician in
selecting appropriate antimicrobial drug therapy.

Dilution Techniques

Quantitative anaerobicin vitro methods can be used to
determine the MIC of fidaxomicin needed to inhibit the growth of the C.
difficile isolates. The MIC provides an estimate of the susceptibility of C.
difficile isolate to fidaxomicin. The MIC should be determined using
standardized procedures.1 Standardized methods are based on an agar
dilution method or equivalent with standardized inoculum concentrations and
standardized concentration of fidaxomicin powder.

Susceptibility Test Interpretive Criteria

In vitro susceptibility test interpretive criteria for
fidaxomicin have not been determined. The relation of the in vitro fidaxomicin
MIC to clinical efficacy of fidaxomicin against C. difficile isolates
can be monitored using in vitro susceptibility results obtained from standardized
anaerobe susceptibility testing methods.

Quality Control Parameters for Susceptibility Testing

In vitro susceptibility test quality control parameters
were developed for fidaxomicin so that laboratories determining the
susceptibility of C. difficile isolates to fidaxomicin can ascertain
whether the susceptibility test is performing correctly. Standardized dilution
techniques require the use of laboratory control microorganisms to monitor the
technical aspects of the laboratory procedures. Standardized fidaxomicin powder
should provide the MIC with the indicated quality control strain shown in Table
4.

Table 4: Acceptable Quality Control Ranges for
Fidaxomicin

Microorganism

MIC Range (μg/mL)

C. difficile (ATCC 700057)

0.03-0.25

Clinical Studies

In two randomized, double-blinded trials, a
non-inferiority design was utilized to demonstrate the efficacy of DIFICID (200
mg twice daily for 10 days) compared to vancomycin (125 mg four times daily for
10 days) in adults with Clostridium difficileassociated diarrhea (CDAD).

Enrolled patients were 18 years of age or older, and
received no more than 24 hours of pretreatment with vancomycin or
metronidazole. CDAD was defined by > 3 unformed bowel movements (or > 200
mL of unformed stool for subjects having rectal collection devices) in the 24
hours before randomization, and presence of either C. difficile toxin A
or B in the stool within 48 hours of randomization. Enrolled patients had
either no prior CDAD history or only one prior CDAD episode in the past three
months. Subjects with life-threatening/fulminant infection, hypotension, septic shock, peritoneal signs, significant dehydration, or toxic megacolon were
excluded.

The demographic profile and baseline CDAD characteristics
of enrolled subjects were similar in the two trials. Patients had a median age
of 64 years, were mainly white (90%), female (58%), and inpatients (63%). The
median number of bowel movements per day was 6, and 37% of subjects had severe
CDAD (defined as 10 or more unformed bowel movements per day or WBC
≥ 15000/mm³). Diarrhea
alone was reported in 45% of patients and 84% of subjects had no prior CDAD
episode.

The primary efficacy endpoint was the clinical response
rate at the end of therapy, based upon improvement in diarrhea or other
symptoms such that, in the Investigator's judgment, further CDAD treatment was
not needed. An additional efficacy endpoint was sustained clinical response 25
days after the end of treatment. Sustained response was evaluated only for
patients who were clinical successes at the end of treatment. Sustained
response was defined as clinical response at the end of treatment, and survival
without proven or suspected CDAD recurrence through 25 days beyond the end of
treatment.

The results for clinical response at the end of treatment
in both trials, shown in Table 5, indicate that DIFICID is non-inferior to
vancomycin based on the 95% confidence interval (CI) lower limit being greater
than the non-inferiority margin of -10%.

The results for sustained clinical response at the end of
the follow-up period, also shown in Table 5, indicate that DIFICID is superior
to vancomycin on this endpoint. Since clinical success at the end of treatment
and mortality rates were similar across treatment arms (approximately 6% in
each group), differences in sustained clinical response were due to lower rates
of proven or suspected CDAD during the follow-up period in DIFICID patients.

* Confidence interval was
derived using Wilson's score method. Approximately 5%-9% of the data in each
trial and treatment arm were missing sustained response information and were
imputed using multiple imputation method.

Restriction Endonuclease
Analysis (REA) was used to identify C. difficile baseline isolates in
the BI group, isolates associated with increasing rates and severity of CDAD in
the US in the years prior to the clinical trials. Similar rates of clinical
response at the end of treatment and proven or suspected CDAD during the
follow-up period were seen in fidaxomicin-treated and vancomycin-treated
patients infected with a BI isolate. However, DIFICID did not demonstrate
superiority in sustained clinical response when compared with vancomycin (Table
6).

Table 6: Sustained Clinical
Response at 25 Days after Treatment by C. difficile REA Group at
Baseline